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Caffeic acid (CA) exhibits a myriad of biological activities including cardioprotective action, antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. On the other hand, CA presents low water solubility and poor bioavailability, which have limited its use for therapeutic applications. The objective of this study was to develop a nanohybrid of zinc basic salts (ZBS) and chitosan (Ch) containing CA (ZBS-CA/Ch) and evaluate its anti-edematogenic and antioxidant activity in dextran and carrageenan-induced paw edema model. The samples were obtained by coprecipitation method and characterized by X-ray diffraction, Fourier transform infrared (FT-IR), scanning electron microscope (SEM) and UV-visible spectroscopy. The release of caffeate anions from ZBS-CA and ZBS-CA/Ch is pH-dependent and is explained by a pseudo-second order kinetics model, with a linear correlation coefficient of R2 ≥ 0.99 at pH 4.8 and 7.4. The in vivo pharmacological assays showed excellent anti-edematogenic and antioxidant action of the ZBS-CA/Ch nanoparticle with slowly releases of caffeate anions in the tissue, leading to a prolongation of CA-induced anti-edematogenic and anti-inflammatory activities, as well as improving its inhibition or sequestration antioxidant action toward reactive species. Overall, this study highlighted the importance of ZBS-CA/Ch as an optimal drug carrier.

Subclinical cardiac dysfunction is associated with smaller total brain volume on magnetic resonance imaging (MRI). To study whether cardiac output relates to regional measurements of grey and white matter structure, older adults (n=326) underwent echocardiogram to quantify cardiac output (L/min) and brain MRI. Linear regressions related cardiac output to grey matter volumes measured on T(1) and white matter hyperintensities assessed on T(2)-FLAIR. Voxelwise analyses related cardiac output to diffusion tensor imaging adjusting for demographic, genetic, and vascular risk factors. Follow-up models assessed a cardiac output x diagnosis interaction with stratification (normal cognition, mild cognitive impairment). Cardiac output interacted with diagnosis, such that lower cardiac output related to smaller total grey matter (p=0.01), frontal lobe (p=0.01), and occipital lobe volumes (p=0.01) among participants with normal cognition. When excluding participants with cardiovascular disease and atrial fibrillation, associations emerged with smaller parietal lobe (p=0.005) and hippocampal volume (p=0.05). Subtle age-related cardiac changes may contribute to disrupt neuronal homeostasis and impact grey matter integrity prior to cognitive impairment.

Visual Abstract, Highlights • Cimaglermin is a recombinant neuregulin that appears to be important for essential cardiac repair processes. • Forty patients with significant left ventricular dysfunction and heart failure were randomized in a phase 1 double blind, placebo controlled, single ascending dose study to examine safety and tolerability. • An infusion of cimaglermin was generally tolerated except for transient nausea and headache. • A dose-limiting toxicity of transient elevated liver transaminases and bilirubin was observed at the highest planned dose. • There was a sustained improvement in left ventricular ejection fraction over 3 months at higher doses tested compared to lower doses or placebo., Summary A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Background Subtle reductions in cardiac output relate to lower cerebral blood flow, especially in regions where Alzheimer's disease pathology first develops. Apolipoprotein E ( APOE )‐ε4 is a genetic susceptibility risk factor for Alzheimer's disease that also moderates vascular damage. This study investigated whether APOE ‐ε4 carrier status modifies the cross‐sectional association between cardiac output and cognition. Methods and Results Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia (n=306, 73±7 years, 42% female) underwent echocardiography to determine cardiac output (L/min), comprehensive neuropsychological assessment, and venous blood draw to determine APOE genotype and ε4 carrier status. Linear regressions related cardiac output to neuropsychological test performance, adjusting for age, sex, education, race/ethnicity, body surface area, cognitive diagnosis, Framingham Stroke Risk Profile, and APOE ‐ε4 status. Main effect models were null ( P >0.19). With identical covariates, models were repeated testing a cardiac output× APOE ‐ε4 status interaction and again stratified by ε4 carrier status. Cardiac output× APOE ‐ε4 status related to naming (β=0.91, P =0.0009), category fluency (β=1.2, P =0.01), information processing speed (β=−5.4, P =0.001), visuospatial skill (β=0.85, P =0.003), and executive function performances (β=0.22, P =0.002). Stratified models suggested that lower cardiac output was associated with worse neuropsychological performances among APOE ‐ε4 carriers. Conclusions APOE ‐ε4 carrier status appears to modify the cross‐sectional association between cardiac output and neuropsychological performance such that lower cardiac output relates to poorer performances among carriers of the ε4 allele. These findings add to increasing evidence that APOE ‐ε4 carrier status has important implications for associations between vascular and brain health in aging adults.

Introduction: Multi-modality imaging is a crucial component of cardiovascular (CV) fellowship training and requires knowledge of CV anatomy for interpretation. We hypothesized that hands-on anatomy education would improve the imaging interpretation skills of CV fellows. Methods: The first-year CV fellowship class completed a hands-on cadaveric anatomy session correlated with clinical imaging. Fellows’ ability to identify CV structures on cardiac imaging was assessed using a 30-question assessment tool administered at baseline and 1 week and 6 months post intervention. Advanced CV fellows (second or third year) who had not attended the session were also tested. Scores were expressed as median [interquartile range]. Results: Among 9 first-year fellows, the majority reported no formal anatomy training since medical school (N = 7) and rated their knowledge of CV anatomy as fair or poor (N = 7) prior to the intervention. The median assessment score was higher 1 week after intervention vs baseline (24 [23-25] vs 19 [17-21]; P = .013) and remained higher than baseline at 6 months (26 [26-28] vs 19 [17-21]; P = .009). The 6-month post-intervention score for first-year fellows was not significantly different than that of senior fellows (n = 10) not exposed to the intervention (26 [26-28] vs 26 [23-27]; P = .434). Conclusions: Gross anatomy instruction improved first-year CV fellows’ interpretation of CV imaging. Anatomic instruction may be a useful adjunct to multi-modality imaging education.

Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

ObjectiveThe optimal management of mitral regurgitation (MR) in patients with cardiomyopathy has been controversial. Minimally invasive fibrillating mitral valve replacement (mini-MVR) might limit postoperative morbidity and mortality by minimizing recurrent MR. We hypothesized that mini-MVR with complete chordal sparing would offer low mortality and halt left ventricular (LV) remodeling in patients with severe cardiomyopathy and severe MR.MethodsFrom January 2006 to August 2009, 65 patients with an LV ejection fraction (LVEF) of ≤35% underwent mini-MVR. The demographic, echocardiographic, and clinical outcomes were analyzed.ResultsThe operative mortality compared with the Society of Thoracic Surgeons-predicted mortality was 6.2% versus 6.6%. It was 5.6% versus 7.4% for patients with an LVEF of ≤20% and 8.3% versus 17.9% among patients with a Society of Thoracic Surgeons-predicted mortality of ≥10%. At a median follow-up of 17 months, no recurrent MR or change in the LV dimensions or LVEF had developed, but the right ventricular systolic pressure had decreased (P = .02). At the first postoperative visit and latest follow-up visit, the New York Heart Association class had decreased from 3.0 ± 0.6 to 1.7 ± 0.7 and 2.0 ± 1.0, respectively (P

Incomplete mitral valve (MV) closure and LV sphericity correlates with functional MR in chronic dilated cardiomyopathy. To assess the mechanism of MR in active myocarditis (M) echocardiograms performed within 5.7 ± 1.2 days of initial RV biopsy in 27 pts with histologically proven M enrolled in the Myocarditis Treatment Trial were analyzed. M pts were stratified into those with mild MR (≤1 +, n = 14) and moderate MR (≥2+, n = 13). LV volume (vol) was measured and a sphericity index (SI) calculated. A value approaching 1 represents increased sphericity. Mitral annular (MA) diameter (d), the distance (DIS) between MV leaflet coaptation and MA plane, and the area enclosed by MVand MA (MVarea) were measured and compared to 20 normal controls. MAd (em) DlS(cm) MVarea (cm 2 ) LVvol (cc/m 2 ) SI Control 23 ± 02 0.32 ± 013 034 ± 013 49.5 ± 79 0.36 ± 0.05 ≤1+ MR 3.1 ± 0.4 * 0.60 ± 0.14 * 1.2 ± 0.45 * 79.7 ± 28.9 * 0.47 ± 0.10 * ≥2+ MR 3.9 ± 0.5 * 0.96 ± 0.18 * 23 ± 0.64 * 78.3 ± 29 * , † 0.48 ± 0.09 * , † * p l 0.0001 compared to control † p = N5 compared to ≤l + MR Conclusion In active M, functional MR does not correlate with increasing LV sphericity. Incomplete MV closure and MA dilatation are more important correlates of MRseverity.